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首页> 外文期刊>The European Journal of Neuroscience >Extrusion of misfolded and aggregated proteins - a protective strategy of aging neurons?
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Extrusion of misfolded and aggregated proteins - a protective strategy of aging neurons?

机译：折叠错误的蛋白质和聚集的蛋白质-老化神经元的保护策略？

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摘要

Cellular senescence is the consequence of repetitive exposures to oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their nucleic acids. Whereas mitotic cells are equipped with efficient cell replacement strategies; postmitotic neurons have - with a few exceptions - no mechanism to substitute dysfunctional cells within a complex neuronal network. Here we propose a potential strategy by which aging neurons contend against abnormal accumulation of damaged/misfolded proteins. The suggested mechanism involves the formation of 'budding-like' extrusions and their subsequent clearance by glia. This hypothesis emerged from our previous investigations of the aged hippocampus revealing layer-specific accumulations of Reelin, a glycoprotein with fundamental roles during brain development and adult synaptic plasticity. We showed that Reelin deposits constitute a conserved neuropathological feature of aging, which is significantly accelerated in adult wild-type mice prenatally exposed to a viral-like infection. Here, we employed two- and three-dimensional immunoelectron microscopy to elucidate their morphological properties, localization and origin in immune challenged vs. control mice. In controls, Reelin-positive deposits were dispersed in the neuropil, some being engulfed by glia. In immune challenged mice, however, significantly more Reelin-immunoreactive deposits were associated with neuritic swellings containing mitochondria, vacuoles and cellular debris, pointing to their intracellular origin and suggesting that 'budding-like' neuronal extrusions of misfolded proteins and glial clearance may represent a protective strategy to counteract aging-associated impairments in proteosomal/lysosomal degradation. Neurons exposed to chronic neuroinflammation with increased levels of misfolded/damaged proteins, however, may fail to combat intraneuronal protein accumulations, a process probably underlying neuronal dysfunction and degeneration during aging.
机译：细胞衰老是反复暴露于氧化应激，扰动的能量稳态，受损蛋白质的积累和核酸损伤的结果。鉴于有丝分裂细胞具备有效的细胞替代策略;除少数例外，有丝分裂后神经元没有替代复杂神经元网络中功能异常的细胞的机制。在这里，我们提出了一种潜在的策略，通过该策略，衰老的神经元可以对抗受损/错误折叠的蛋白质的异常积累。所建议的机制涉及“类芽状”挤压物的形成及其随后的神经胶质清除。这个假设来自我们以前对老年海马的研究，揭示了层特异性的Reelin积累，Reelin是一种糖蛋白，在大脑发育和成人突触可塑性中具有基本作用。我们显示，Reelin沉积物构成了衰老的保守神经病理学特征，该衰老在出生前暴露于病毒样感染的成年野生型小鼠中明显加速。在这里，我们采用了二维和三维免疫电子显微镜，以阐明它们的形态特征，定位和起源于免疫攻击小鼠与对照小鼠。在对照中，Reelin阳性沉积物分散在神经纤维中，有些被神经胶质吞没。然而，在受到免疫攻击的小鼠中，明显更多的Reelin免疫反应性沉积物与包含线粒体，液泡和细胞碎片的神经肿胀有关，这表明它们是细胞内起源的，这表明错误折叠的蛋白质和神经胶质清除的“芽状”神经元挤压可能代表了抵制蛋白质组/溶酶体降解中与衰老相关的损伤的保护性策略。然而，暴露于慢性神经发炎的神经元的错误折叠/损坏的蛋白质水平增加，可能无法抵抗神经元内蛋白质的积累，这可能是衰老期间神经元功能障碍和变性的过程。

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